Molecular mechanisms of host-derived CCL5 mediated mammary tumor growth

描述（由申请人提供）：乳腺癌是北美女性中最常见的恶性肿瘤类型。乳腺癌患者中更高的CCL 5产生与更严重的疾病进展相关，表明CCL 5在乳腺癌进展中的重要作用。最近，我们发现CCL 5缺陷小鼠对乳腺肿瘤生长和转移具有高度抵抗性，肿瘤中浸润的巨噬细胞数量减少。因此，我们假设宿主CCL 5通过吸引巨噬细胞迁移到肿瘤中来促进乳腺肿瘤的进展。阻断荷瘤宿主中的CCL 5信号传导可能成为乳腺癌治疗的新靶点。CCL 5是由多种细胞产生的趋化因子，包括T细胞、巨噬细胞、成纤维细胞和肿瘤细胞。它通过将T细胞、巨噬细胞和嗜酸性粒细胞募集到炎症部位而在炎症中起重要作用。CCL 5已被证明能够帮助肿瘤血管生成，抑制T细胞反应并促进乳腺癌的生长。使用同基因乳腺肿瘤模型，最近的一项研究表明，肿瘤来源的CCL 5与肿瘤进展有关，这表明宿主来源的CCL 5对乳腺癌的生长和转移很重要。我们的初步数据表明，CCL 5基因缺陷的小鼠（CCL 5-KO）对肿瘤诱导的死亡具有抗性，并且很少发生肺转移。与这些发现一致，野生型小鼠中CCL 5的中和抑制肿瘤生长和肺转移。通过流式细胞术和免疫荧光染色对肿瘤的进一步分析揭示了CCL 5-KO小鼠肿瘤中巨噬细胞的显著减少。我们的数据首次提供了直接证据，表明宿主来源的CCL 5对乳腺肿瘤的生长和转移至关重要。由于宿主衍生的CCL 5在促进乳腺肿瘤进展中的机制在很大程度上是未知的，我们建议研究宿主衍生的CCL 5介导巨噬细胞浸润到肿瘤中的机制以及肿瘤细胞诱导宿主巨噬细胞中CCL 5表达的分子机制。我们的长期目标是阐明宿主CCL 5促进乳腺癌生长和转移的细胞，分子和免疫机制，并最终开发以肿瘤特异性方式靶向CCL 5的治疗药物。 公共卫生相关性：乳腺癌是北美妇女中最常见的恶性肿瘤。乳腺癌患者中更高的CCL 5产生与更严重的疾病进展相关，表明CCL 5在乳腺癌进展中的重要作用。我们的目标是阐明宿主CCL 5促进乳腺癌生长和转移的细胞，分子和免疫机制，并最终开发以肿瘤特异性方式靶向CCL 5的治疗药物。

DESCRIPTION (provided by applicant): Breast cancer is the most common type of malignant tumor among women in North America. Higher CCL5 production in breast cancer patients is associated with more progressive disease, indicating an important role of CCL5 in breast cancer progression. Recently, we have found that CCL5 deficient mice are highly resistant to mammary tumor growth and metastasis, with decreased numbers of macrophages infiltrated in the tumor. Therefore, we hypothesize that host CCL5 promotes mammary gland tumor progression by attracting macrophages migrated into the tumor. Blocking CCL5 signaling in a tumor-bearing host may serve as a new therapeutic target for breast cancer treatments. CCL5 is a chemokine produced by a variety of cells, including T cells, macrophages, fibroblasts and tumor cells. It plays an important role in inflammation by recruiting T cells, macrophages and eosinophils to inflammatory sites. CCL5 has been shown to be able to help in tumor angiogenesis, inhibit T cell responses and enhance growth of breast cancers. Using a syngeneic mammary tumor model, a recent study demonstrates that tumor-derived CCL5 is dispensable for tumor progression, suggesting it is the host-derived CCL5 which is important for breast cancer growth and metastasis. Our preliminary data demonstrates that mice genetically deficient in CCL5 (CCL5-KO) are resistant to tumor-induced death and develop few lung metastases. Consistent with these findings, neutralization of CCL5 in wild-type mice suppresses tumor growth and lung metastases. Further analyses of tumors by flow cytometry and immunofluorescence staining reveal a significant decrease of macrophages in the tumors of CCL5-KO mice. Our data provides direct evidence for the first time that host-derived CCL5 is essential for mammary tumor growth and metastasis. Since the mechanisms of host-derived CCL5 in promoting mammary tumor progression are largely unknown, we propose to investigate the mechanisms whereby host-derived CCL5 mediates macrophage infiltration into the tumors and the molecular mechanisms by which tumor cells induce CCL5 expression in host macrophages. Our long-term goal is to elucidate the cellular, molecular and immunologic mechanisms by which host CCL5 promotes breast cancer growth and metastasis, and to ultimately develop therapeutic agents that target CCL5 in a tumor-specific manner. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common type of malignant tumor among women in North America. Higher CCL5 production in breast cancer patients is associated with more progressive disease, indicating an important role of CCL5 in breast cancer progression. Our goal is to elucidate the cellular, molecular and immunologic mechanisms by which host CCL5 promotes breast cancer growth and metastasis, and to ultimately develop therapeutic agents that target CCL5 in a tumor-specific manner.